Indazole derivatives as inhibitors of hormone sensitive lipase

ABSTRACT

The present invention relates to indazole derivatives of the general formulae I or II having the meanings indicated in the description, to the pharmaceutically useful salts thereof and the use thereof as drugs.

The present invention relates to indazole derivatives of the generalformulae I or II, the pharmaceutically usable salts thereof and the usethereof as drugs.

Indazole derivatives for stimulating the cannabinoid receptor aredescribed in WO 03/035005 and derivatives of 3-amino-indazole carboxylicacid in DE 24 58 965. Furthermore phenyl carbamoyl-indazole derivativesare described in WO 2004/046090 and 3-amino5-phenyl-indazole-1-carboxylic acid amide in U.S. 2004/0097485, whichhowever have been published after the filing date of the priorityapplication.

The invention relates to indazole derivatives of the general formulae Ior II,

in which the meanings are:

-   W is —(C═O)—, —(S═O)— or —(SO₂)—;-   X is ═C(—R)— or ═N—;-   Y is —O— or —N(R1);-   R is hydrogen, halogen, (C₁-C₆)-alkyl,    (C₁-C₃)-alkyloxy-(C₁-C₃)-alkylene, hydroxy, (C₁-C₆)-alkylmercapto,    amino, (C₁-C₆)-alkylamino, di-(C₂-C₁₂)-alkylamino,    mono-(C₁-C₆)-alkylaminocarbonyl, di-(C₂-C₈)-alkylaminocarbonyl,    COOR4, cyano, trifluoromethyl, (C₁-C₆)-alkylsulfonyl,    (C₁-C₆)-alkylsulfinyl, aminosulfonyl, nitro, pentafluorosulfanyl,    (C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, CO—NR2R3, O—CO—NR2R3,    O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-alkylene-CO—OH, O—CO—(C₁-C₆)-alkylene-CO—NR2R3 or    unsubstituted or mono- or poly-F-substituted (C₁-C₆)-alkyloxy;-   R1 is H, (C₁-C₆)-alkyl or benzyl;-   R2 is H, (C₁-C₆)-alkyl, (C₁-C₄)-alkyl-phenyl or (C₆-C₁₀)-aryl,    wherein said (C₁-C₄)-alkyl-phenyl or (C₆-C₁₀)-aryl is optionally    substituted by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy, hydroxy,    (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,    di-(C₂-C₁₂)-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,    di-(C₂-C₈)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,    trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkylsulfonyl,    aminosulfonyl, nitro or tetramethyl-tetrahydronaphthalene;-   R3 is H or (C₁-C₆)-alkyl; or-   R2 and R3 may form together with the nitrogen atom carrying them a    monocyclic, saturated or partially unsaturated 4- to 7-membered ring    system or a bicyclic saturated or partially unsaturated 8- to    14-membered ring system, whose individual members of the ring    systems may be replaced by one to three atoms or atomic groups from    the series —CHR5-, —CR5R5-, —(C═R5)⁻, —NR5-, —C(═O)—, —O—, —S—,    —SO—, —SO₂—, with the proviso that two units from the series —O—,    —S—, —SO—, —SO₂— may not be adjacent;-   R4 is hydrogen, (C₁-C₆)-alkyl or benzyl;-   R5 is (C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl or    cyclopropylene;    and the physiologically tolerated salts thereof as well as its    tautomeric forms    with the proviso that in compounds of the formula (I) with W═CO-   a) R2 and R3 together with the nitrogen atom carrying them form a    monocyclic or bicyclic ring system if Y=N(R1) with R1=H or    (C₁-C₆)-alkyl or-   b) YR1, R2 and R3 do not have simultaneously the following meanings:    YR1=OH, R2=(C₆-C₁₀)-aryl which may be substituted and R3=H.

Preferred compounds of the formulae I and II are those in which

-   Y is —O—,    or those in which-   W is —(C═O)—.

Preferred compounds of the formulae I and II are further those in which

-   NR2R3 is a monocyclic saturated 5- to 6-membered ring system    comprising in position 4 an atom or atomic member from the series    —CHR5-, —CR5R5-, —(C═R5)-, —NR5-, —O—, —S—.

Further preferred compounds of the formulae I and II are those in which

-   X in position 4, 5 and 7 is ═C(—R)— with R=hydrogen.

Particularly preferred compounds of the formula I or II are those inwhich

-   W is —(C═O)—;-   X is ═C(—R)— or ═N—;-   Y is —O—;-   R is hydrogen, halogen, (C₁-C₆)-alkyl, hydroxy, amino, COOR4,    trifluoromethyl, (C₁-C₆)-alkylsulfonyl, nitro, pentafluorosulfanyl,    (C₆-C₁₀)-aryl, CO—NR2R3, O—CO—NR2R3 or    O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl;-   R1 is H, (C₁-C₆)-alkyl or benzyl;-   R2 is (C₁-C₆)-alkyl, benzyl, (C₆-C₁₀)-aryl or    tetramethyl-tetrahydronaphthalene;-   R3 is H or (C₁-C₆)-alkyl; or-   R2 and R3 together with the nitrogen atom carrying them may form a    monocyclic saturated 5- to 6-membered ring system or a bicyclic    saturated or partially unsaturated 9- to 10-membered ring system    whose individual members of the ring systems may be replaced by one    to two atoms or atomic groups from the series —CHR5-, —CR5R5-,    —(C═R5)-, —NR5-, —O—, —S—, with the proviso that two units from the    series —O—, —S— may not be adjacent;-   R4 is hydrogen, (C₁-C₆)-alkyl or benzyl;-   R5 is (C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl or    cyclopropylene.

Particularly preferred compounds of the formula I are further those inwhich

-   W is —(C═O)—;-   X is ═C(—R)— or ═N—;-   Y is —O—;-   R is hydrogen, halogen, nitro, hydroxy or (C₁-C₆)-alkyl;-   R1 is H or (C₁-C₆)-alkyl;-   R2 is (C₁-C₆)-alkyl, benzyl or (C₆-C₁₀)-aryl;-   R3 is (C₁-C₆)-alkyl; or-   R2 and R3 together with the nitrogen atom carrying them may form a    monocyclic saturated 5- to 6-membered ring system or a bicyclic    saturated or partially unsaturated 9- to 10-membered ring system    whose individual members of the ring systems may be replaced by an    atom or an atomic group from the series —CHR5- or —NR5-; and-   R5 is (C₁-C₆)-alkyl or cyclopropyl.

Particularly preferred compounds of the formula II are also those inwhich

-   W is —(C═O)—;-   X is ═C(—R)— or ═N—;-   Y is —O—;-   R is hydrogen, halogen, (C₁-C₆)-alkyl, hydroxy, amino, COOR4,    trifluoromethyl, (C₁-C₆)-alkylsulfonyl, nitro, pentafluorosulfanyl,    (C₆-C₁₀)-aryl, CO—NR2R3, O—CO—NR2R3 or    O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl;-   R1 is H, (C₁-C₆)-alkyl or benzyl;-   R2 is (C₁-C₆)-alkyl, (C₆-C₁₀)-aryl or    tetramethyl-tetrahydronaphthalene;-   R3 is H or (C₁-C₆)-alkyl; or-   R2 and R3 together with the nitrogen atom carrying them may form a    monocyclic saturated 5- to 6-membered ring system or a bicyclic    saturated or partially unsaturated 9- to 10-membered ring system    whose individual members of the ring systems may be replaced by one    to two atoms or atomic groups from the series —CHR5-, —CR5R5-,    —(C═R5)-, —NR5-, —O—, —S—, with the proviso that two units from the    series —O—, —S— may not be adjacent;-   R4 is hydrogen, (C₁-C₆)-alkyl or benzyl; and-   R5 is (C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl or    cyclopropylene.

Very particularly preferred compounds of the formula II are those inwhich

-   NR2R3 is piperidine which comprises the atomic member CHR5 in    position 4.

The invention relates to compounds of the formulae I or II in the formof their salts, racemates, racemic mixtures and pure enantiomers, and totheir diastereomers and mixtures thereof.

The alkyl radicals in the substituents R, R1, R2, R3, R4, R5 may beeither straight-chain or branched. Halogen is fluorine, chlorine,bromine or iodine, in particular fluorine or chlorine.

Aryl means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to10 ring atoms which may is substituted independently with one to foursubstituents, preferably one or two substituents as described herein.

Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atomshaving at least one aromatic ring containing one, two or three ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.

Unless otherwise indicated, the terms used herein are defined asfollows:

“Patient” means a warm blooded animal, such as for example rat, mice,dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

“Therapeutically effective amount” means a quantity of the compoundwhich is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts)and alkaline earth metal salts (such as magnesium and calcium salts) andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion likewise belong withinthe framework of the invention as useful intermediates for thepreparation or purification of pharmaceutically acceptable salts and/orfor use in nontherapeutic, for example in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Ior II of the invention, for example an ester, which on administration toa mammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or II or an active metabolitethereof.

Physiologically functional derivatives include prodrugs of the compoundsof the invention as, for example, described in H. Okada et al., Chem.Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivoto a compound of the invention. These prodrugs may themselves be activeor not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I or II” hereinafter refer tocompound(s) of the formula I or II as described above, and their salts,solvates and physiologically functional derivatives as described herein.

The citation of any reference herein should not be construed as anadmission that such reference is available as “Prior Art” to the instantapplication.

The present invention is not to be limited in scope by the specificembodiments describe herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

Use

The compounds of the invention of the general formulae I or II have asurprising inhibitory effect on hormone sensitive lipase, HSL, anallosteric enzyme in adipocytes which is inhibited by insulin and isresponsible for the breakdown of fats in fat cells and thus fortransferring fat constituents into the blood stream. Inhibition of thisenzyme is therefore equivalent to an insulin-like effect of thecompounds of the invention, eventually leading to reduction of freefatty acids in the blood and of blood glucose. They can therefore beemployed for metabolic derangements such as, for example, fornon-insulin-dependent diabetes mellitus, for diabetic syndrome and fordirect pancreatic damage.

Compounds of this type are particularly suitable for the treatmentand/or prevention of

-   1.    -   disorders of fatty acid metabolism and glucose utilization        disorders    -   disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are        -   hyperglycemia,        -   improvement in insulin resistance,        -   improvement in glucose tolerance,        -   protection of the pancreatic β cells        -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations,    -   low HDL cholesterol concentration    -   low ApoA lipoprotein concentrations    -   high LDL cholesterol concentrations    -   small dense LDL cholesterol particles    -   high ApoB lipoprotein concentrations-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   obesity (excess weight), including central obesity    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Other disorders or conditions in which inflammatory reactions or    cell differentiation may for example be involved are:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   pancreatitis    -   other inflammatory states    -   retinopathy    -   adipose cell tumors    -   lipomatous carcinomas such as, for example, liposarcomas    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas etc    -   acute and chronic myeloproliferative disorders and lymphomas    -   angiogenesis    -   neurodegenerative disorders    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease    -   erythemato-squamous dermatoses such as, for example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermatitis    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, lichen planus    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   high blood pressure    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)    -   lypodystrophy and lipodystrophic states, also for treating        adverse drug effects (e.g. following medicaments for treating        HIV or tumours)        Formulations

The amount of a compound of the invention necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of bodyweight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, from 0.1 ng to 10 mg,typically from 1 ng to 10 mg, per milliliter. Single doses may contain,for example, from 1 mg to 10 g of the active ingredient. Thus, ampoulesfor injections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, tablets or capsules, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I or II may be usedas the compound itself, but they are preferably in the form of apharmaceutical composition with an acceptable carrier. The carrier must,of course, be acceptable in the sense that it is compatible with theother ingredients of the composition and is not harmful for thepatient's health. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet, which may contain from 0.05% to 95% by weight of the activeingredient. Other pharmaceutically active substances may likewise bepresent, including other compounds of the invention. The pharmaceuticalcompositions of the invention can be produced by one of the knownpharmaceutical methods, which essentially consist of mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Ior II used in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contain a defined amount of thecompound of formula I or II; as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one ormore surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I or II with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I or II, which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I or II with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single pouches whichare suitable for long-term close contact with the patient's epidermis.Such pouches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formulae I and II are distinguished by favorableeffects on metabolic disorders. They beneficially influence lipid andsugar metabolism, in particular they lower the triglyceride level andare suitable for the prevention and treatment of type II diabetes andarteriosclerosis and the diverse sequalae thereof.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, favorable effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formulaI or II in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Examples which may be mentioned are:

Antidiabetics

Suitable antidiabetics are disclosed for example in the Rote Liste 2001,chapter 12 or in the USP Dictionary of USAN and International DrugNames, US Pharmacopeia, Rockville 2001. Antidiabetics include allinsulins and insulin derivatives such as, for example, Lantus® (seewww.lantus.com) or Apidra®, and other fast-acting insulins (see U.S.Pat. No. 6,221,633), GLP-1 receptor modulators as described in WO01/04146 or else, for example, those disclosed in WO 98/08871 of NovoNordisk A/S.

The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassiumchannel openers such as, for example, those disclosed in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism and lead to achange in the blood lipid composition, compounds which reduce foodintake, PPAR and PXR modulators and active ingredients which act on theATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with substances which influence hepaticglucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188).

In one embodiment, the compounds of the formula I or II are administeredin combination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of the formula I or II are administeredin combination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I or II are administeredin combination with a biguanide such as, for example, metformin.

In a further embodiment, the compounds of the formula I or II areadministered in combination with a meglitinide such as, for example,repaglinide.

In one embodiment, the compounds of the formula I or II are administeredin combination with a thiazolidinedione such as, for example,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I or II are administeredin combination with a DPPIV inhibitor as described, for example, inWO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO 02/38541,WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021 ((2S,4S)₄-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I or II are administeredin combination with compounds with an inhibitory effect on SGLT-1 and/or2, as disclosed directly or indirectly for example in PCT/EP03/06841,PCT/EP03/13454 and PCT/EP03/13455.

In one embodiment, the compounds of the formula I or II are administeredin combination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compounds of the formula I or II are administeredin combination with more than one of the aforementioned compounds, e.g.in combination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an HMGCoA reductase inhibitor suchas lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a bile acid reabsorption inhibitor(see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897,U.S. Pat. No. 6,277,831, EP 0683 773, EP 0683 774).

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a polymeric bile acid adsorbentsuch as, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a cholesterol absorption inhibitoras described for example in WO 0250027, or ezetimibe, tiqueside,pamaqueside.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

In one embodiment, the compounds of the formula I or II are administeredin combination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6.) Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a PPARalpha agonist.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a mixed PPAR alpha/gamma agonistsuch as, for example, AZ 242 (Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl)-2-ethoxypropionicacid), BMS 298585(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine)or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169,WO96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO00/64876.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a CETP inhibitor, e.g. CP-529, 414(torcetrapib).

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an MTP inhibitor such as, forexample, implitapide.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a lipoprotein(a) antagonist.

Antiobesity Agents

In one embodiment of the invention, the compounds of the formula I or IIare administered in combination with a lipase inhibitor such as, forexample, orlistat.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In a further embodiment, the compounds of the formula I or II areadministered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormoneand Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amidehydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin4-ylurea hydrochloride(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanolhydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), TRH agonists (see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the further active ingredient isleptin.

In one embodiment, the further active ingredient is dexamphetamine,amphetamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I or II are administeredin combination with medicaments having effects on the coronarycirculation and the vascular system, such as, for example, ACEinhibitors (e.g. ramipril), medicaments which act on theangiotensin-renine system, calcium antagonists, beta blockers etc.

In one embodiment, the compounds of the formula I or II are administeredin combination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I or II are administeredin combination with medicaments which are employed for cancer therapyand cancer prevention.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention.

The activity of the compounds of the invention of the formulae I or IIwas tested in the following enzyme assay system:

Substrate Preparation:

Preparation of NAG (NBD monoacyl glyceride) substrate:

6 mg of phosphatidylcholine and 6 mg of phosphatidylinositol are eachdissolved in 1 ml of chloroform. 10 mg of NAG are dissolved in 1 ml ofchloroform. Two parts of phosphatidylinositol solution (e.g. 83.5 μl)and one part of phosphatidylcholine solution (e.g. 41.5 μl) and 100 μlof NAG solution are pipetted together into plastic scintillation vessels(final concentration in the assay: 0.0375 mg of phospholipid/ml; 0.05mg/NAG/ml). The chloroform (225 μl total volume) is completely removedby passing a stream of N2 over it. The dried substrate can be stored at4° C. for up to 3 days. To prepare the phospholipid vesicles/micelleswith intercalated NAG (on the day of the assay), the dried substrate istaken up in 20 ml of assay buffer (25 mM Tris/HCl, pH 7.4; 150 mM NaCl)and two ultrasound treatments with an ultrasonic probe (Branson SonifierType II, standard microtip): 1st treatment setting 2, 2×1 min, inbetween 1 min on ice each time; 2nd treatment setting 4, 2×1 min, inbetween 1 min on ice each time. During this procedure, the color of thesubstrate solution changes from yellow (extinction maximum 481 nm) tored (extinction maximum 550 nm) owing to intercalation of NAG betweenthe phospholipid molecules in the vesicles/micelles. Before use assubstrate (within the next 2 h), the solution is incubated on ice for 15min.

Indirect NAG Assay:

The assay is carried out in 1.5 ml Eppendorf vessels or 96-well platesat 30° C. for 60 min. To find HSL inhibitors, 10 μl of the testsubstance are introduced into assay buffer (25 mM Tris/HCl, pH 7.4; 150mM NaCl) in the presence of 16.6% DMSO. 180 μl of the substrate solution(20 μg/ml phosphatidylcholine, 10 μg/ml phosphatidylinositol, 50 μg/mlNAG in assay buffer) are added. After preincubation at 30° C. for 15min, 20 μl of the enzyme solution in assay buffer (diluted 1- to 4-foldare pipetted in, and the extinction at 480 nm is immediately measured ina cuvette photometer (0.5 ml cuvette) or microtiter plate reader. Afterincubation at 30° C. for 60 min, the extinction is measured again. Theincrease in extinction at 480 nm is a measure of the enzymic activity.Under standard conditions, 20 μg of partially purified HSL lead to achange of 0.4=4000 arb. units in extinction.

Direct NAG Assay:

As an alternative to measurement of the change in extinction of thesubstrate solution, the products of the HSL reaction are investigated byphase separation/thin-layer chromatography. For this purpose, 1.3 ml ofmethanol/chloroform/heptane (10:9:7) and then 0.4 ml of 0.1 M NaOH areadded to the incubation mixture (200 μl total volume, see indirect NAGassay) in 2 ml Eppendorf vessels. After vigorous mixing (10 sec), phaseseparation is initiated by centrifugation (800×g, 20 min, roomtemperature). Equivalent volumes (e.g. 0.4 ml) are taken from theaqueous upper phase, and the extinction at 481 nm is determined in aphotometer. For thin-layer chromatography, the aqueous phase is dried(SpeedVac) and then taken up in 50 μl of tetrahydrofuran. 5 μl samplesare loaded onto silica gel Si-60 plates (Merck). The chromatography iscarried out with 78 ml of diethyl ether/22 ml of petroleum ether/1 ml ofglacial acetic acid as mobile phase. The amount of liberated fluorescentNBD-fatty acid is determined by Phosphorimaging (Molecular Dynamics,Storm 840 and ImageQuant Software) at an excitation wavelength of 460 nmand emission wavelength of 540-560 nm.

Enzyme Preparation:

Preparation of the partially purified HSL:

Isolated rat fat cells are obtained from epididymal adipose tissue fromuntreated male rats (Wistar, 220-250 g) by collagenase treatment inaccordance with published methods (e.g. S. Nilsson et al., Anal.Biochem. 158, 1986, 399-407; G. Fredrikson et al., J. Biol. Chem. 256,1981, 6311-6320; H. Tornquist et al., J. Biol. Chem. 251, 1976,813-819). The fat cells from 10 rats are washed three times by flotationwith 50 ml of homogenization buffer (25 ml Tris/HCl, pH 7.4, 0.25 Msucrose, 1 mM ETDA, 1 mM DTT, 10 μg/ml leupeptin, 10 μg/ml antipain, 20μg/ml pepstatin) each time and finally taken up in 10 ml ofhomogenization buffer. The fat cells are homogenized in aTeflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1500 rpmand 15° C. The homogenate is centrifuged (Sorvall SM24 tubes, 5000 rpm,10 min, 4° C.). The subnatant between the layer of fat at the top andthe pellet is removed and the centrifugation is repeated. The subnatantresulting therefrom is centrifuged again (Sorvall SM24 tubes, 20 000rpm, 45 min, 4° C.). The subnatant is removed, and 1 g ofheparin-Sepharose (Pharmacia-Biotech, CL-6B, washed 5× with 25 mMTris/HCl, pH 7.4, 150 mM NaCl) is added. After incubation at 4° C. for60 min (shaking at intervals of 15 min), the mixture is centrifuged(Sorvall SM24 tubes, 3000 rpm, 10 min, 4° C.). The supernatant isadjusted to pH 5.2 by adding glacial acetic acid and is incubated at 4°C. for 30 min. The precipitates are collected by centrifugation (SorvallSS34, 12 000 rpm, 10 min, 4° C.) and suspended in 2.5 ml of 20 mMTris/HCl, pH 7.0, 1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 μg/mlleupeptin/pepstatin/antipain. The suspension is dialyzed against 25 mMTris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg/ml leupeptin, pepstatin,antipain at 4° C. overnight and then loaded onto a hydroxiapatite column(0.1 g per 1 ml of suspension, equilibrated with 10 mM potassiumphosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column is washed withfour volumes of equilibration buffer at a flow rate of 20 to 30 ml/h.The HSL is eluted with one volume of equilibration buffer containing 0.5M potassium phosphate and then dialyzed (see above) and concentrated 5-to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4° C. Thepartially purified HSL can be stored at −70° C. for 4 to 6 weeks.

Assay:

To prepare the substrate, 25-50 μCi of [3H]trioleoylglycerol (intoluene), 6.8 μmol of unlabeled trioleoylglycerol and 0.6 mg ofphospholipids (phosphatidylcholine/phosphatidylinositol 3:1 w/v) aremixed, dried with N2 and then taken up in 2 ml of 0.1 M KPi (pH 7.0) byultrasound treatment (Branson 250, microtip, setting 1-2, 2×1 min withan interval of 1 min). After addition of 1 ml of KPi and renewedultrasound treatment (4×30 sec on ice with intervals of 30 sec), 1 ml of20% BSA (in KPi) is added (final concentration of trioleoylglycerol 1.7mM). For the reaction, 100 μl of substrate solution are pipetted into100 μl of HSL solution (HSL prepared as above, diluted in 20 mM KPi, pH7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 μg/ml pepstatin, 10 μg/mlleupeptin) and incubated at 37° C. for 30 min. Addition of 3.25 ml ofmethanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M K2CO3, 0.1M boric acid (pH 10.5) is followed by thorough mixing and finallycentrifugation (800×g, 20 min). After phase separation, one equivalentof the upper phase (1 ml) is removed and the radioactivity is determinedby liquid scintillation measurement.

Evaluation:

Substances are normally tested in four independent mixtures. Theinhibition of the HSL enzymatic activity by a test substance isdetermined by comparing with an uninhibited control reaction. The IC50is calculated from an inhibition plot with min. 10 concentrations of thetest substance. The GRAPHIT, Elsevier-BIOSOFT software package is usedto analyze the data.

The compounds of Examples 1 to 101 showed inhibitions in the IC₅₀ range1 nM-1 μM in this assay.

The compounds of the invention of the general formulae I or II areprepared by methods known per se, e.g. by acylation of substituted orunsubstituted indazoles III with carbamoyl chlorides IV (method A), orin two stages by reacting indazoles III with phosgene or equivalentssuch as trichloromethyl chlorocarbonate or ditrichloromethyl carbonateand further reaction of the resulting indazolecarbonyl chloride withamines or anilines (method B). For compounds in which R3 is hydrogen,the indazoles III can also be reacted with the appropriate isocyanatesR2-N═C═O.

Since acids are usually liberated in these reactions, it is advisable toadd bases such as pyridine, triethylamine, sodium hydroxide solution oralkali metal carbonates for expedition. The reactions can be carried outin wide temperature ranges. It has usually proved to be advantageous tooperate at from 0° C. to the boiling point of the solvent used. Examplesof solvents employed are methylene chloride, THF, DMF, toluene, ethylacetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrousconditions are used, strong bases such as lithium hydride, sodiumhydride or potassium tert-butoxide in aprotic solvents such as THF orDMF have also proved suitable.

The indazoles employed as starting compounds III, or correspondingaza-substituted derivatives, are commercially available or can beprepared by processes known from the literature (e.g. L. Baiocchi, G.Corsi Synthesis (1978), 633-648, I. Sekikawa et al. J. Het. Chem.(1973), 931-932).

The compounds of the general formulae I and II are separated andpurified by chromatographic methods known per se.

The examples detailed below serve to illustrate the invention without,however, restricting it.

EXAMPLES Example 1 1H-Indazol-3-yl 4-methylpiperidine-1-carboxylate

300 mg (2.24 mmol) of 1H-indazol-3-ol were dissolved in 25 ml of THF andcooled to −20° C.: 1.3 ml (2.46 mmol) of phosgene in toluene (20percent) were added dropwise and the reaction mixture was stirred for 90min, during which it warmed to room temperature. The reaction mixturewas concentrated and evacuated once again with a few ml of toluene. Theresidue was dissolved in 15 ml of THF, 265 μl (2.2 mmol) of4-methylpiperidine were added dropwise and the mixture was stirred atroom temperature for 3 h, concentrated and purified by preparative HPLC(PR18, acetonitrile/water 0.1% TFA). Yield: 347 mg (60%), M+H+: 260.4.

Example 2 4-Methylpiperidine-1-carbonyl Chloride

9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mol) oftriethylamine were dissolved in 100 ml of THC and, at −30° C., 54.9 ml(100 mmol) of phosgene in toluene (20 percent) were added, and themixture was stirred for 2.5 h, during which it warmed to roomtemperature. The reaction mixture was concentrated, the residue wasmixed with methylene chloride and filtered off, and the filtrate wasconcentrated. The crude product (12.7 g) was reacted without furtherpurification.

Example 3 4-Fluoro-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate

100 mg (0.66 mmol) of 4-fluoro-1H-indazol-3-ol and 116.8 mg (0.72 mmol)of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 10 ml ofpyridine were heated under reflux for 4 h and left to stand overnight.Addition of 24 mg of 4-methyl-piperidine-1-carbonyl chloride wasfollowed by heating under reflux for a further 2 h while the pyridinewas distilled off in vacuo, and the residue was dissolved in water andextracted with ethyl acetate. The organic phase was concentrated andpurified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield:56 mg (31%), M+H+: 278.1.

Example 4 1-Methyl-1H-indazolyl-3-yl 4-methylpiperidine-1-carboxylate

80.1 mg (0.31 mmol) of 1H-indazol-3-yl 4-methylpiperidine-1-carboxylate(Example 1), 38.1 mg (0.34 mmol) of potassium-tert-butoxide and 48.2 mg(0.34 mmol) of iodomethane were stirred at room temperature for 48 h.The solvent was distilled off in vacuo, and the residue was dissolved inwater and extracted with ethyl acetate. The organic phase wasconcentrated and purified by preparative HPLC (PR18, acetonitrile/water0.1% TFA). Yield: 7 mg (8%), M+H+: 274.1.

Example 5

100 mg (0.56 mmol) of 6-nitro-1H-indazol-3-ol and 135.3 mg (0.83 mmol)of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 10 ml ofpyridine were heated under reflux for 5 h and left to stand overnight.Pyridine was distilled off in vacuo, and the residue was dissolved inwater and extracted with ethyl acetate. The organic phase wasconcentrated and purified by preparative HPLC (PR18, acetonitrile/water0.1% TFA). Yield: 5 mg (3%) of A:(3-hydroxy-6-nitroindazol-1-yl)-(4-methyl-piperidin-1-yl)methanone,M+H+: 305.1 and 64 mg (38%) of B: 6-nitro-1H-indazol-3-yl4-methylpiperidine-1-carboxylate, M+H+: 305.1.

Example 6 5-Nitro-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate

200 mg (1.12 mmol) of 5-nitro-1H-indazol-3-ol and 180.4 mg (1.67 mmol)of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 20 ml ofpyridin were heated under reflux for 5 h and left to stand overnight.Pyridine was distilled off in vacuo, and the residue was dissolved inwater and extracted with ethyl acetate. The organic phase wasconcentrated and purified by preparative HPLC (PR18, acetonitrile/water0.1% TFA). Yield: 48 mg (14%), M+H+: 304.99.

Example 7 6-Amino-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate

30 mg (0.1 mmol) of 6-nitro-1H-indazol-3-yl4-methylpiperidine-1-carboxylate (Example 5B) in 15 ml of ethanol werehydrogenated in the presence of 10% palladium/carbon under a hydrogenpressure of 2 bar at room temperature for 2.5 h. The catalyst wasfiltered off with suction, and the filtrate was concentrated. Yield: 21mg (76%), M+H+: 275.2.

Example 8

Example 1 was repeated with 2 g (14.9 mmol) of 1H-indazol-3-ol. In thiscase it was possible to isolate A: 1H-indazol-3-yl4-methylpiperidine-1-carboxylate also the isomeric products B:(3-hydroxyindazol-1-yl)-(4-methylpiperidin-1-yl)methanone and C:2-(4-methylpiperidine-1-carbonyl)-1,2-dihydroindazol-3-one.

Example 9 1H-Pyrazolo[3,4-b]pyridin-3-yl 4-methylpiperidine-1-carboxylate

a) 1H-Pyrazolo[3,4-b]pyridin-3-ol: 5 g (26.94 mmol) of ethyl2-chloronicotinate and 4.76 g (80.82 mmol) of hydrazine hydrate (85percent) in 10 ml of ethanol were heated under reflux for 6 h. Thereaction mixture was concentrated. Yield: 3.5g (96%), M+H+: 135.9.

b) 300 mg (2.2 mmol) of 1H-pyrazolo[3,4-b]pyridin-3-ol and 538.2 mg (3.3mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 25 ml ofpyridine were heated under reflux for 4 h and left to stand overnight.Addition of 24 mg of 4-methylpiperidine-1-carbonyl chloride werefollowed by further heating under reflux for 2 h, the pyridine wasdistilled off in vacuo, and the residue was dissolved in water andextracted with ethyl acetate. The organic phase was concentrated andpurified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield:99 mg (17%), M+H+: 261.28.

Example 10

500 mg (2.16 mmol) of 1H-indazol-3-ylamine; compound with sulfuric acidand 419.3 mg (2.59 mmol) of 4-methylpiperidine-1-carbonyl chloride(Example 2) and 300 μl (4.32 mmol) of triethylamine in 30 ml of pyridinewere heated under reflux for 5 h and left to stand overnight. Additionof 302 μl of triethylamine and and 390 mg of4-methylpiperidine-1-carbonyl chloride was followed by heating for afurther 2.5 h. Pyridine was distilled off in vacuo, and the residue wasdissolved in water and extracted with ethyl acetate. The organic phasewas concentrated and purified by preparative HPLC (PR18,acetonitrile/water 0.1% TFA). Yield: 55 mg (10%) of A:4-methylpiperidine-1-carboxylic acid (1H-indazol-3-yl)amide, M+H+: 259.1and 36.4 mg (7%) of B:(3-aminoindazol-1-yl)-(4-methylpiperidin-1-yl)methanone, M+H+: 259.1.

Example 11 4-Trifluoromethylpiperidine-1-carbonyl Chloride

Carbonic acid ditrichloromethyl ester (840 mg, 2.83 mmol) were dissolvedin 30 ml of methylene chloride and, in an ice bath, 2.06 ml (25.24 mmol)of pyridine were slowly added. After 30 min, 4-trifluoromethylpiperidinehydrochloride (1.45 g, 7.65 mmol) was slowly added in portions. Afterremoval of the ice bath, stirring was continued for 90 min, theprecipitate was filtered off and washed with n-heptane, and the filtratewas concentrated. The resulting product (1.9 g) still contains some saltand was reacted further directly.

Example 12 4-Trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-yl Ester

4-Methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diol (1 g, 6.05 mmol),4-trifluoromethyl-piperidine-1-carbonyl chloride (1.436 g, 6.6 mmol) andtriethylamine (1.68 ml, 12.11 mmol) were stirred in 25 ml of pyridine atroom temp for 1 h. Addition of 0.5 ml of triethylamine was followed bystirring for 2 h, concentration and addition of ethyl acetate and water.The resulting precipitate was filtered off with suction and dried.Yield: 765 mg (37%) of 4-trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. The organicphase was separated off, concentrated and purified by preparative HPLC(PR18, acetonitrile/water 0.1% TFA). Yield: 96 mg (5%) of4-trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. M+H+: 345.13;102 mg (3%) of 4-trifluoromethylpiperidine-1-carboxylic acid4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-ylester, M+H+: 524.20; 106 mg (3%) of4-trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-ylester, M+H+: 524.52; 54 mg (1.3%) of4-trifluoromethylpiperidine-1-carboxylic acid4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-6-ylester, M+H+: 703.36.

Example 13 4-Methylpiperazine-1-carboxylic Acid4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-ylEster; Compound with Trifluoroacetic Acid

4-Trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-yl ester (300 mg, 0.87mmol), 4-methylpiperazine-1-carbonyl chloride hydrochloride (191 mg,0.96 mmol) and triethylamine (0.48 ml, 3.48 mmol) were stirred in 10 mlof pyridine at room temp. for 5 h. Addition of 0.4 ml of triethylamineand 100 mg of 4-methylpiperazine-1-carbonyl chloride hydrochloride wasfollowed by stirring for 1 h, concentration and addition of ethylacetate and water and adjustment to pH 8. The organic phase wasseparated off (multiple extraction), concentrated and purified bypreparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 125 mg(25%) of 4-methylpiperazine-1-carboxylic acid4-methyl-3-(4-trifluoromethyl-piperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-ylester; compound with trifluoroacetic acid, M+H+: 471.24; 82 mg (13%)4-trifluoromethylpiperidine-1-carboxylic acid6-hydroxy-4-methyl-1-(4-methylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-ylester; compound with trifluoroacetic acid, M+H+: 471.27.

Example 14 6-Nitro-1H-indazol-3-ol

2-Fluoro-4-nitrobenzoic acid methyl ester (5 g, 25.11 mmol) andhydrazine hydrate (1.34 ml, 27.62 mmol) were dissolved in 250 ml ofethanol and heated under reflux for 11 h. A further 0.26 ml of hydrazinehydrate were added and heated under reflux for a further 6 h, and themixture was concentrated and ethyl acetate and water were added. Theprecipitated residue was filtered off with suction and dried.Purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA)resulted in 1.39 g of product, M+H+: 180.05.

Example 15 6-Fluoro-1H-indazol-3-ol

2-Amino-4-fluorobenzoic acid (25 g, 161.2 mmol) were suspended in 250 mlof water and 39 ml of conc. hydrochloric acid. At 0° C., sodium nitrite(11.2 g, 161.2 mmol) in 30 ml of water were added dropwise at below 10C.After 30 min at room temp., sodium sulfite (69 g, 400 mmol) in 250 ml ofwater were added. After stirring for 2 h, 30 ml of conc. hydrochloricacid were added, and the mixture was left to stand overnight. It wasthen heated under reflux for 9 h, cooled and adjusted to pH 5.5 withsodium bicarbonate. The precipitate was filtered off with suction anddried.

Yield: 19.8 g, (81%), M+H+: 152.94.

Example 16 3-Hydroxy-1H-indazole-6-carboxylic Acid

2-Aminoterephthalic acid dimethyl ester (5 g, 23.9 mmol) were dissolvedin 40 ml of water and 6 ml of conc. hydrochloric acid. At 0° C., sodiumnitrite (1.65 g, 23.9 mmol) in 5 ml of water were added dropwise atbelow 10° C. After 30 min at room temp., sodium sulfite (11.02 g, 87.42mmol) in 40 ml of water were added. After stirring for 1 h, 10 ml ofconc. hydrochloric acid were added, and the mixture was left to standovernight. It was then heated at 80° C. for 24 h, cooled and adjusted topH 5.5 with sodium hydroxide solution. The precipitate was filtered offwith suction and dried.

Yield: 2.29 g, (54%), M+H+: 179.04.

Example 17 3-Hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylicacid

5-Amino-2H-pyrazol-3-ol (3.1 g, 31.6 mmol) were suspended in 100 ml ofmethanol. Then sodium methoxide (5.1 g, 95 mmol) and 2,4-dioxopentanoicacid ethyl ester (5 g, 31.6 mmol) were added, and the mixture was heatedup under reflux for 12 h. The solvent was removed in a rotaryevaporator, water was added to the residue, the precipitate was filteredoff with suction, and the filtrate was adjusted to pH 6 with dilutehydrochloric acid. The precipitated product (both precipitates) wasfiltered off with suction and dried. Yield: 4.9 g (70%), M+H+: 194.09.

The following compounds were prepared in analogy to the describedexamples: Exam- ple Name M+H+ 18 3-Methylpiperidine-1-carboxylic acid1H-indazol-3-yl 260.2 ester 19(3,4-Dihydro-2H-quinolin-1-yl)-(3-hydroxy-indazol-1- 294.3 yl)-methanone20 (3-Hydroxy-indazol-1-yl)-pyrrolidin-1-yl-methanone 232.3 21(3-Hydroxy-indazol-1-yl)-thiomorpholin-4-yl- 264.4 methanone 22(3,4-Dihydro-1H-isoquinolin-2-yl)-(3-hydroxy- 294.5indazol-1-yl)-methanone 23 3-Hydroxy-indazole-1-carboxylic acid methyl-268.3 phenyl-amide 24 3-Methyl-piperidine-1-carboxylic acid 1-methyl-1H-274.4 indazol-3-yl ester 25(3-Methoxy-indazol-1-yl)-(3-methyl-piperidin-1-yl)- 274.4 methanone 263-Hydroxy-indazole-1-carboxylic acid dibutylamide 290.16 27Diethyl-carbamic acid 1H-indazol-3-yl ester 234.11 28Diisopropyl-carbamic acid 1H-indazol-3-yl ester 262.13 29Piperidine-1-carboxylic acid 1H-indazol-3-yl ester 246.10 30(1,3-Dihydro-isoindol-2-yl)-(3-hydroxy-indazol-1-yl)- 280.12 methanone31 4-Methyl-piperidine-1-carboxylic acid 6- 328.16trifluoromethyl-1H-indazol-3-yl ester 324-Methyl-piperidine-1-carboxylic acid 6-fluoro-1H- 278.13 indazol-3-ylester 33 4-Methyl-piperidine-1-carboxylic acid 6-chloro-1H- 294.06indazol-3-yl ester 34 4-Methyl-piperidine-1-carboxylic acid 6-methyl-1H-274.12 indazol-3-yl ester 35(6-Chloro-3-hydroxy-indazol-1-yl)-(4-methyl- 294.12piperidin-1-yl)-methanone 36(3-Hydroxy-indazol-1-yl)-(octahydro-isoindol-2-yl)- 286.16 methanone 37Octahydro-isoindole-2-carboxylic acid 1H-indazol-3- 286.17 yl ester 383,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1H- 294.13 indazol-3-ylester 39 4-Methyl-piperidine-1-carboxylic acid 6-chloro-4- 309.14methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 40(3-Hydroxy-pyrazolo[3,4-b]pyridin-1-yl)-(4-methyl- 261.17piperidin-1-yl)-methanone 41 4-Methyl-piperidine-1-carboxylic acid4-methyl-3-(4- 416.24 methyl-piperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl ester 42 4-Methyl-piperidine-1-carboxylic acid6-hydroxy-4- 291.20 methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 43(6-Fluoro-3-hydroxy-indazol-1-yl)-(4-methyl- 278.18piperidin-1-yl)-methanone 44(6-Fluoro-3-hydroxy-indazol-1-yl)-(octahydro- 304.20isoindol-2-yl)-methanone 45(3,4-Dihydro-1H-isoquinolin-2-yl)-(6-fluoro-3- 312.17hydroxy-indazol-1-yl)-methanone 46 Octahydro-isoindole-2-carboxylic acid6-fluoro-1H- 304.21 indazol-3-yl ester 47 Piperidine-1-carboxylic acid6-fluoro-1H-indazol-3-yl 264.17 ester 48 Methyl-phenyl-carbamic acid6-fluoro-1H-indazol-3- 286.17 yl ester 493,4-Dihydro-1H-isoquinoline-2-carboxylic acid 6- 312.13fluoro-1H-indazol-3-yl ester 50 4-Methyl-piperidine-1-carboxylic acid1H- 261.15 pyrazolo[4,3-c]pyridin-3-yl ester 514-Methyl-piperidine-1-carboxylic acid 6-bromo-1H- 338.08 indazol-3-ylester 52 3-(4-Methyl-piperidine-1-carbonyloxy)-1H-indazole- 318.176-carboxylic acid methyl ester 53(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen- 364.8 2-yl)-carbamicacid 1H-indazol-3-yl ester 54 3,4-Dihydro-1H-isoquinoline-2-carboxylicacid 6- 343.16 chloro-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 554-Methyl-piperidine-1-carboxylic acid 6- 329.19trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 56(6-Fluoro-3-methoxy-indazol-1-yl)-(4-methyl- 292.20piperidin-1-yl)-methanone 57 4-Methyl-piperidine-1-carboxylic acid5,6-difluoro- 296.25 1H-indazol-3-yl ester 58(3,4-Dihydro-1H-phthalazin-2-yl)-(6-fluoro-3- 313.15hydroxy-indazol-1-yl)-methanone 59(6-Chloro-3-hydroxy-4-methyl-pyrazolo[3,4- 343.12b]pyridin-1-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone 604-Methyl-piperidine-1-carboxylic acid 1-benzyl-6- 381.27hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 614-Methyl-piperidine-1-carboxylic acid 6- 338.17methanesulfonyl-1H-indazol-3-yl ester 624-Methyl-piperidine-1-carboxylic acid 6-hydroxy-1H- 277.15pyrazolo[3,4-b]pyridin-3-yl ester 63(3,6-Dihydroxy-pyrazolo[3,4-b]pyridin-1-yl)-(4- 277.15methyl-piperidin-1-yl)-methanone 64(6-Chloro-3-hydroxy-4-methyl-pyrazolo[3,4- 309.13b]pyridin-1-yl)-(4-methyl-piperidin-1-yl)-methanone 65 Succinic acidmethyl ester 4-methyl-3-(4-methyl- 405.26piperidine-1-carbonyloxy)-1H-pyrazolo[3,4- b]pyridin-6-yl ester 664-Methyl-piperazine-1-carboxylic acid 6-fluoro-1H- 279.15 indazol-3-ylester; compound with trifluoro-acetic acid 673,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1H- 295.18pyrazolo[3,4-b]pyridin-3-yl ester 684,4-Difluoro-piperidine-1-carboxylic acid 6-fluoro- 300.251H-indazol-3-yl ester 69 4,4-Difluor-piperidine-1-carboxylic acid4-methyl-3- 438.31 (4-methyl-piperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl ester 706,7-Dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic 318.11 acid6-fluoro-1H-indazol-3-yl ester 71 Piperidine-1,4-dicarboxylic acid4-benzyl ester 1-(6- 398.26 fluoro-1H-indazol-3-yl)ester 72Thiomorpholine-4-carboxylic acid 6-fluoro-1H- 282.13 indazol-3-yl ester73 4-Trifluoromethyl-piperidine-1-carboxylic acid 6- 332.16fluoro-1H-indazol-3-yl ester 74 2,6-Dimethyl-morpholine-4-carboxylicacid 6-fluoro- 294.18 1H-indazol-3-yl ester 754-Phenyl-piperazine-1-carboxylic acid 6-fluoro-1H- 341.21 indazol-3-ylester 76 Morpholine-4-carboxylic acid 6-fluoro-1H-indazol-3- 266.15 ylester 77 3,4-Dihydro-1H-phthalazine-2-carboxylic acid 6- 313.14fluoro-1H-indazol-3-yl ester; compound with trifluoro-acetic acid 784,4-Difluoro-piperidine-1-carboxylic acid 6-hydroxy- 313.174-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 794,4-Difluoro-piperidine-1-carboxylic acid 6-chloro-4- 331.14methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 804-Methyl-piperidine-1-carboxylic acid 4,6-difluoro- 296.171H-indazol-3-yl ester 81 Piperidine-1,4-dicarboxylic acidmono-(6-fluoro-1H- 308.20 indazol-3-yl)ester 824-Fluoro-piperidine-1-carboxylic acid 6-fluoro-1H- 282.10 indazol-3-ylester 83 4-Cyclopropyl-piperazine-1-carboxylic acid 6-fluoro- 305.241H-indazol-3-yl ester 84 Piperazine-1,4-dicarboxylic acid benzyl ester6- 399.13 fluoro-1H-indazol-3-yl ester 854-Fluoro-piperidine-1,4-dicarboxylic acid 4-ethyl 354.13 ester1-(6-fluoro-1H-indazol-3-yl)ester 86(4-Cyclopropyl-piperazin-1-yl)-(6-fluoro-3-hydroxy- 305.35indazol-1-yl)-methanone 87 4,4-Dimethyl-piperidine-1-carboxylic acid6-fluoro- 292.19 1H-indazol-3-yl ester 884-Methyl-piperidine-1-carboxylic acid 6-fluoro-1- 292.13methyl-1H-indazol-3-yl ester 894-(3,4-Dimethyl-phenyl)-piperazine-1-carboxylic 351.17 acid1H-indazol-3-yl ester 90 4-Trifluoromethyl-piperidine-1-carboxylic acid6- 263.07 chloro-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 914-Methyl-piperidine-1-carboxylic acid 5-fluoro-1H- 278.22 indazol-3-ylester 92 4-Trifluoromethyl-piperidine-1-carboxylic acid 4- 470.18methyl-3-(4-methyl-piperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl ester 934-Cyclopropylidene-piperidine-1-carboxylic acid 6- 302.14fluoro-1H-indazol-3-yl ester 94 4-Cyclopropyl-piperazine-1-carboxylicacid 6- 318.21 hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 95Piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-[4- 536.40methyl-3-(4-methyl-piperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl] ester 96 3-Methyl-piperidine-1-carboxylicacid 6- 386.32 pentafluorosulfanyl 1H-indazol-3-yl ester 974-Methyl-3-(4-methyl-piperidine-1-carbonyloxy)-1H- 319.17pyrazolo[3,4-b]pyridine-6-carboxylic acid 984-Methyl-piperidine-1-carboxylic acid 4-methyl-6-(4- 400.26methyl-piperidine-1-carbonyl)-1H-pyrazolo[3,4- b]pyridin-3-yl ester 994-Methyl-piperidine-1-carboxylic acid 4-methyl-6- 351.34phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester 1004-Trifluoromethyl-piperidine-1-carboxylic acid 4,6- 350.11difluoro-1H-indazol-3-yl ester 101 4-Methyl-piperidine-1-carboxylic acid6-(4-methyl- 385.25 piperidine-1-carbonyl)-1H-indazol-3-yl ester 1026-Chloro-3-hydroxy-indazole-1-carboxylic acid 302.10 benzylamide 1036-Chloro-3-hydroxy-indazole-1-carboxylic acid 296.16 hexylamide

1. An indazole derivative of the formulae I or II

in which the meanings are: W is —(C═O)—, —(S═O)— or —(SO₂)—; X is═C(—R)— or ═N—; Y is —O— or —N(R1); R is hydrogen, halogen,(C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy-(C₁-C₃)-alkylene, hydroxy,(C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-(C₂-C₁₂)-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₈)-alkylaminocarbonyl, COOR4, cyano, trifluoromethyl,(C₁-C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₆-C₁₀)-aryl, (C₅-C₁₂)-heteroaryl, CO—NR2R3,O—CO—NR2R3, O—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl,O—CO—(C₁-C₆)-alkylene-CO—OH, O—CO—(C₁-C₆)-alkylene-CO—NR2R3 orunsubstituted or mono- or poly-F-substituted (C₁-C₆)-alkyloxy; R1 is H,(C₁-C₆)-alkyl or benzyl; R2 is H, (C₁-C₆)-alkyl, (C₁-C₄)-alkyl-phenyl or(C₆-C₁₀)-aryl, wherein said (C₁-C₄)-alkyl-phenyl or (C₆-C₁₀)-aryl isoptionally substituted by halogen, (C₁-C₆)-alkyl, (C₁-C₃)-alkyloxy,hydroxy, (C₁-C₆)-alkylmercapto, amino, (C₁-C₆)-alkylamino,di-(C₂-C₁₂)-alkylamino, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₈)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkylsulfonyl, aminosulfonyl,nitro or tetramethyl-tetrahydronaphthalene; R3 is H or (C₁-C₆)-alkyl; orR2 and R3 may form together with the nitrogen atom carrying them amonocyclic, saturated or partially unsaturated 4- to 7-membered ringsystem or a bicyclic saturated or partially unsaturated 8- to14-membered ring system, whose individual members of the ring systemsmay be replaced by one to three atoms or atomic groups from the series—CHR5-, —CR5R5-, —(C═R5)-, —NR5-, —C(═O)—, —O—, —S—, —SO—, —SO₂—, withthe proviso that two units from the series, —S—, —SO—, —SO₂— may not beadjacent; R4 is hydrogen, (C₁-C₆)-alkyl or benzyl; R5 is (C₁-C₆)-alkyl,halogen, trifluoromethyl, COOR4, cyclopropyl or cyclopropylene; and thephysiologically tolerated salts thereof as well as its tautomeric formswith the proviso that in compounds of the formula (I) with W═CO a) R2and R3 together with the nitrogen atom carrying them form a monocyclicor bicyclic ring system if Y═N(R1) with R1=H or (C₁-C₆)-alkyl or b) YR1,R2 and R3 do not have simultaneously the following meanings: YR1=OH,R2=(C₆-C₁₀)-aryl which may be substituted and R3=H.
 2. The indazolederivative of claim 1, wherein Y is —O—.
 3. The indazole derivative ofclaim 1, wherein W is —(C═O)—.
 4. The indazole derivative of claim 1wherein NR2R3 is a monocyclic saturated 5- to 6-membered ring systemwhich comprises in position 4 an atom or atomic member from the series—CHR5-, —CR5R5-, —(C═R5)-, —NR5-, —O— or —S—.
 5. The indazole derivativeof claim 1, wherein X in position 4, 5 and 7 is ═C(—R)— with R=hydrogen.6. The indazole derivative of claim 1, wherein W is —(C═O)—; X is═C(—R)— or ═N—; Y is —O—; R is hydrogen, halogen, (C₁-C₆)-alkyl,hydroxy, amino, COOR4, trifluoromethyl, (C₁-C₆)-alkylsulfonyl, nitro,pentafluorosulfanyl, (C₆-C₁₀)-aryl, CO—NR2R3, O—CO—NR2R3 orO—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl; R1 is H, (C₁-C₆)-alkyl orbenzyl; R2 is (C₁-C₆)-alkyl, benzyl, (C₆-C₁₀)-aryl ortetramethyl-tetrahydronaphthalene; R3 is H or (C₁-C₆)-alkyl; or R2 andR3 together with the nitrogen atom carrying them may form a monocyclicsaturated 5- to 6-membered ring system or a bicyclic saturated orpartially unsaturated 9- to 10-membered ring system whose individualmembers of the ring systems may be replaced by one to two atoms oratomic groups from the series —CHR5-, —CR5R5-, —(C═R5)-, —NR5-, —O—,—S—, with the proviso that two units from the series —O—, —S— may not beadjacent; R4 is hydrogen, (C₁-C₆)-alkyl or benzyl; and R5 is(C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl orcyclopropylene.
 7. The indazole derivative of claim 1, wherein W is—(C═O)—; X is ═C(—R)— or ═N—; Y is —O—; R is hydrogen, halogen, nitro,hydroxy or (C₁-C₆)-alkyl; R1 is H or (C₁-C₆)-alkyl; R2 is (C₁-C₆)-alkyl,benzyl or (C₆-C₁₀)-aryl; R3 is (C₁-C₆)-alkyl; or R2 and R3 together withthe nitrogen atom carrying them may form a monocyclic saturated 5- to6-membered ring system or a bicyclic saturated or partially unsaturated9- to 10-membered ring system whose individual members of the ringsystems may be replaced by an atom or an atomic group from the series—CHR5-, —NR5-; and R5 is (C₁-C₆)-alkyl or cyclopropyl.
 8. The indazolederivative of claim 1, wherein W is —(C═O)—; X is ═C(—R)— or ═N—; Y is—O—; R is hydrogen, halogen, (C₁-C₆)-alkyl, hydroxy, amino, COOR4,trifluoromethyl, (C₁-C₆)-alkylsulfonyl, nitro, pentafluorosulfanyl,(C₆-C₁₀)-aryl, CO—NR2R3, O—CO—NR2R3 orO—CO—(C₁-C₆)-alkylene-CO—O—(C₁-C₆)-alkyl; R1 is H, (C₁-C₆)-alkyl orbenzyl; R2 is (C₁-C₆)-alkyl, (C₆-C₁₀)-aryl ortetramethyl-tetrahydronaphthalene; R3 is H or (C₁-C₆)-alkyl; or R2 andR3 together with the nitrogen atom carrying them may form a monocyclicsaturated 5- to 6-membered ring system or a bicyclic saturated orpartially unsaturated 9- to 10-membered ring system whose individualmembers of the ring systems may be replaced by one to two atoms oratomic groups from the series —CHR5-, —CR5R5-, —(C═R5)-, —NR5-, —O—,—S—, with the proviso that two units from the series —O—, —S— may not beadjacent; R4 is hydrogen, (C₁-C₆)-alkyl or benzyl; and R5 is(C₁-C₆)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl orcyclopropylene.
 9. The indazole derivative of claim 1, wherein NR2R3 ispiperidine which comprises the atomic member CHR5 in position
 4. 10. Apharmaceutical composition comprising one or more of the indazolederivatives of claim 1 and a pharmaceutically acceptable carrier.
 11. Amethod of inhibiting hormone sensitive lipase in a patient in needthereof comprising administering to said patient one or more of theindazole derivatives of claim
 1. 12. A method of inhibiting hormonesensitive lipase in a patient in need thereof comprising administeringto said patient one or more indazole derivatives of claim 1 incombination with one or more active ingredients which have favorableeffects on metabolic disturbances or disorders associated therewith. 13.A method of inhibiting hormone sensitive lipase in a patient in needthereof comprising administering to said patient a therapeuticallyeffective amount of one or more indazole derivatives of claim 1 incombination with one or more antidiabetics.
 14. A method of inhibitinghormone sensitive lipase in a patient in need thereof comprisingadministering to said patient a therapeutically effective amount of oneor more indazole derivatives of claim 1 in combination with one or morelipid modulators.
 15. A method of treating or preventing disorders offatty acid metabolism and glucose utilization disorders in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of one or more indazole derivatives of claim
 1. 16. Amethod of treating or preventing disorders involving insulin resistancecomprising administering to a patient in need thereof a therapeuticallyeffective amount of one or more indazole derivatives of claim
 1. 17. Amethod of treating or preventing diabetes mellitus and the sequelaeassociated therewith comprising administering to a patient in needthereof a therapeutically effective amount of one or more indazolederivatives of claim
 1. 18. A method of treating or preventingdyslipidemias and their sequelae comprising administering to a patientin need thereof a therapeutically effective amount of one or moreindazole derivatives of claim
 1. 19. A method of treating or preventingconditions associated with metabolic syndrome comprising administeringto a patient in need thereof a therapeutically effective amount of oneor more indazole derivatives of claim
 1. 20. A method of treating orpreventing disorders of fatty acid metabolism and glucose utilizationdisorders in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of one or more indazolederivatives of claim 1 in combination with at least one further activeingredient for the treatment and/or prevention of disorders of fattyacid metabolism and glucose utilization disorders.
 21. A method oftreating or preventing disorders involving insulin resistance comprisingadministering to a patient in need thereof a therapeutically effectiveamount of one or more indazole derivatives of claim 1 in combinationwith at least one further active ingredient for the treatment and/orprevention of disorders in which insulin resistance is involved.